Polymers, including but not limited to linear polymers and star polymers, particularly those comprising one or more monomers selected from the group consisting of ethylene glycol, lactide, glycolate, glycolide, and caprolactone, have found use as delivery vehicles for small-molecule drugs. Particularly, the small molecule may be entrapped within the polymer structure, and the drug may be released into a patient's body gradually over an extended period of time following administration of the polymer formulation to the patient.
During the synthesis of a polymer, particularly when the synthesis is initiated by a reducing sugar or a sugar alcohol and/or catalyzed by, e.g., a tin catalyst, decomposition byproducts typically form and may be present in a mixture with the polymer. The presence of such decomposition byproducts may result in the polymer mixture having a color, particularly a brownish color, rather than being clear or white. Polymers containing glycolides may also have an undesirable color, particularly a brown color. The presence of these impurities is generally undesirable, particularly in polymer compositions intended for parenteral administration to a patient, because the impurities may cause irritation to the patient or may interfere with intended release characteristics of the drug from the polymer delivery vehicle. There is thus a need in the art to effectively remove these impurities.
European Patent 469,520, entitled “Polylactide preparation and purification,” issued 5 Feb. 1992 to Prikoszovich (“Prikoszovich”), discloses a method for the purification and color removal of glucose-initiated star polymers comprising lactide and glycolide monomers and is incorporated herein by reference in its entirety. In the method disclosed by Prikoszovich, a solution of the star polymer in, e.g., acetone is combined with activated charcoal and allowed to remain in contact with the activated charcoal for a period of time before being filtered. Prikoszovich discloses that a brown solution of a lactide/glycolide star copolymer was rendered colorless and had very low levels of tin catalyst after treatment by the disclosed method.
Attempts by the present inventors to reproduce the results described by Prikoszovich revealed several problems inherent in the method of Prikoszovich. Fine carbon particles utilized in the polymer solution rapidly clogged the filters, even when filters with large surface areas were used; this problem was only partially mitigated by the use of granulated carbon.
The present inventors attempted to modify the method of Prikoszovich by loading granular activated carbon into stainless steel pipes to form a carbon bed and slowly recirculating the polymer solution through the carbon bed. Although this modification was successful in preventing carbon fines from clogging the filter and in removing color and tin catalyst from the polymer solution, the modified method was complicated and unreliable, required long circulation times and large quantities of activated carbon, and generated large quantities of flammable spent solvent.
Additionally, when metal catalysts are employed in polymer synthesis methods, the resulting polymer is often covalently bonded or otherwise tightly bound to the metal catalyst, which may be problematic when the polymer is intended for administration to a patient due to the potential toxicity of the metal catalyst. There is thus a need in the art to remove metal catalysts, including but not limited to tin catalysts, from solutions of polymers, especially from polymer solutions intended for administration to a patient.
It is therefore advantageous to develop a method for purification, and particularly for decolorization and/or catalyst removal, of polymer solutions, including but not limited to solutions of linear polymers and star polymers, that is simpler, more reliable, more efficient, and safer than the methods of the prior art. It is further advantageous to develop such a method that is suitable in scale to purify large quantities of polymer solution to a very high level of purity, as may be appropriate, by way of non-limiting example, for polymer solutions intended for parenteral administration to a patient. It is still further advantageous to develop methods that effectively remove metal catalysts, including but not limited to tin catalysts, from polymer solutions, whereby metal removal may be performed separately from or in conjunction with decolorization.